Serious systemic fungal infections are rare, but with antimicrobial resistance on the rise and only a limited number of approved drugs available, it is imperative that new treatment options are developed soon. Fortunately, things may be about to change, as several promising new drugs are close to market approval.
Developing effective, nontoxic antifungals is very difficult due to fungi being eukaryotic organisms and thus more closely related to humans than other microbes, such as bacteria. Currently, there are only three classes of antifungal drugs on the market: polyenes, azoles, and echinocandins. This makes treatment options limited for patients with systemic fungal infections like invasive aspergillosis or candidiasis.
Over the last 20 years, there has been much publicity about antimicrobial resistance and the problems it can cause. However, the majority of this information has focused on antibacterial resistance and to a lesser extent antiviral resistance. While often overlooked, antifungal resistance is also a serious, emerging problem.
Although localized fungal infections of the skin, nails, and genital areas are fairly common in humans, we have a natural resistance to developing serious, systemic fungal infections. This means that most patients who become infected with a fungus have another medical condition that compromises their immune system.
For example, it is estimated that 25% of severe Covid-19 patients have contracted invasive fungal infections, particularly after being treated with immune-suppressing drugs, such as dexamethasone or IL-6 inhibitors.
To turn the tables and provide very sick patients with more treatment options, a small number of biotech companies in the UK and US are developing innovative new treatment options.
Limitations of antifungals
The options that clinicians currently have to treat patients with systemic fungal infections are limited. “Because they’re eukaryotes, many of the potentially available targets that are essential for growth or reproduction in fungi resemble the [equivalent] target in humans, and so are really not available as a drug target,” explained Jeffrey Stein, CEO of US-based antifungal developer Cidara.
Polyenes, the oldest of the three main antifungal drug classes, target fungal cholesterol. The most commonly used member of this class is amphotericin B. While it radically improved options for patients when it was approved in the late 1950s, it is associated with serious and sometimes life-threatening side effects, including fever, inflammation of the heart, and kidney problems. As a result, these drugs have limited applicability.
The first azoles were approved in the early 1980s. They have been the most successful antifungal to date, mostly because they are available in an oral formulation. But they also come with problems. These drugs inhibit cytochrome p450 — a ‘drug-metabolizing’ liver enzyme needed to detoxify human blood.
“You typically are susceptible to a fungal infection when you’re hospitalized for something else. And if you’re hospitalized for something else, you’re typically on a number of other drug regimens,” said Stein. As this enzyme metabolizes many drugs, drug-drug interactions are a problem with azoles and can contribute to adverse events such as liver toxicity.
Echinocandins target glucan synthase, an enzyme in the cell wall of fungi that is unique to fungi. This makes them stand out as it means they have low levels of toxicity compared to the other two drug classes.
“[Echinocandins] do have one liability, as they need to be administered once a day in a one-hour long infusion,” explained Stein. When you consider that some patients might need treatment for months, this can be very challenging.
Emergence of resistance
Antifungal resistance has been creeping up for some time. “When people actually look and test resistance, they find it, and it’s been recorded globally now. Rates between 5 and 10% are quite common,” explained Mike Birch, COO of UK-based antifungal biotech F2G.
“It’s probably less common in terms of the percent of resistant isolates than in the antibacterial field, primarily because the genetic mechanisms of resistance are different. Bacteria mutate more readily and spread those mutations more readily than fungi. But if you look at the data it’s incrementally increasing over time.”
Resistance to drugs in the azole class has become a particular problem, due largely to excessive use of azoles in agriculture. Flowers and fruits are particularly susceptible to fungal infections and low concentrations of azoles have been sprayed on fields in Western countries for many years.
A notable example of this is in the Netherlands, which has many tulip and flower farms. Aspergillus is a very common fungus that primarily lives on plants but can infect and severely damage the lungs of immune-compromised people. Intensive spraying of the flower fields with low concentration azoles has led to the Netherlands having some of the highest rates of azole-resistant invasive aspergillosis in the world.
To put the scale of the problem into perspective, non-resistant invasive aspergillosis has a mortality rate of up to 50% after treatment. This figure goes up to 80% if the fungus is resistant to azoles.
“There are so few antifungals available that when you start to have a class that has become resistant you suddenly lose half of your weapons,” emphasized Marco Taglietti, CEO of US-based antifungal biotech Scynexis.
Recognizing that antifungal resistance was becoming a problem, regulations came in between 2012 and 2014 in both Europe and the US recommending that azoles should no longer be used as first-line therapy for fungal infections, such as aspergillosis or invasive candidemia, where Candida yeast infects the blood.
However, Stein believes many healthcare practitioners have continued to prescribe azoles to their patients, despite this advice, because of the convenience of the oral formulation. “Many patients with candidemia, depending on the hospital setting, may actually get a prescription of an azole just to prevent hospitalization. So that drives resistance.”
New options on the horizon
Innovation has been fairly slow in the antifungal space since the first echinocandins were approved 20 years ago. However, four biotech companies have been working hard to get new treatment options onto the market. Each has a new antifungal that is currently being tested in either phase II or III trials: fosmanogepix from US biotech Amplyx, rezafungin from California-based Cidara, olorofim from UK biotech F2G and ibrexafungerp from New Jersey-based Scynexis.
“These four are really promising,” said Oliver Cornely, an antifungal expert and professor at the University of Cologne in Germany. “There are some others that are highly interesting and should be developed further, but are owned by companies that ran out of money, or do have funds but can only slowly develop their compound. So anything else is a bit far off in terms of marketing authorization.”
Cidara’s rezafungin, which is currently at phase III, is a new addition to the echinocandin class. It targets a broad range of different fungal infections. Like the others of this class, it has to be given intravenously, but it can be administered once a week at a high dose as opposed to daily.
“One of the reasons why the other three currently available echinocandins cannot be administered at higher exposures is that they are hydrolyzed relatively rapidly once they are administered intravenously,” explained Stein. “If [clinicians] dose any higher, they run into liver toxicity issues due to the breakdown products. Rezafungin, which is stable, does not break down.”
The three other drugs being developed are all first-in-class. Scynexis’ broad-spectrum antifungal ibrexafungerp, the first in the fungerp class, is the most advanced and is currently at phase III. It is notable for being an oral formulation.
“The fact it is oral is the wow factor of this antifungal,” commented Scynexis CEO, Marco Taglietti. “The treatment of severe invasive fungal infection is something that actually requires long treatment and therefore having a product that can be given orally and allows a patient to be discharged is actually a big, important advancement.”
“[Ibrexafungerp] is often associated with echinocandins, because it has a similar mechanism of action. But the compound is active against some isolates that are resistant towards echinocandins. So it’s not the same,” said Cornely.
F2G’s olorofim is at phase II and is the first in the orotomide drug class. It targets an enzyme called dihydroorotate dehydrogenase and stops the synthesis of pyrimidine, which is needed for fungal growth. The drug candidate is effective against aspergillus and a variety of rare mold and fungal infections with very limited treatment options, but is not effective against yeasts such as Candida.
The F2G team is developing both an oral and an intravenous version of olorofim, which has recently been granted breakthrough designation by the FDA based on good early tolerability and efficacy data.
“It looks very, very promising and could be the solution for some pathogens where there is absolutely no treatment,” commented Cornely about olorofim.
Amplyx’s fosmanogepix is also in phase II trials and targets a different fungal enzyme called Gwt1. This enzyme is needed to move and fix mannoprotein to the outer cell wall in fungi, which is needed to maintain their structure and to evade the host immune system. Crucially, Gwt1 is specific to fungi and fosmanogepix does not bind to human cells and cause adverse effects.
In trials to date, it has shown broad efficacy, including against Candida strains resistant to other therapies, and appears to be well tolerated. Also recognizing the value of having an oral formulation, the company is developing both an oral and an intravenous version of the drug.
Developing antifungal drugs is difficult and time-consuming, but it seems that the perseverance and patience of these four companies may soon be rewarded.
“It’s a field that’s been somewhat in the shadows for a long time,” Ian Nicholson, CEO of F2G, told me. He is hoping that the current global pandemic may help highlight the importance of this area of drug development.
“In some of the indications we’re dealing with, without treatment, the mortality rates are 90 to 100%, so the need for new drugs here is really desperate.”
Although antifungal resistance is slower to develop than antibacterial resistance, the small overall number of available drugs makes resistance a huge problem. Limiting agricultural use of azoles could be one answer, but the susceptibility of plants to these infections is high and could result in a devastating loss of food crops.
Another answer is to boost innovation in this sector and develop more antifungal drugs.
“All of these clinical trials are quite challenging and take a long time, which is a contributing factor of why there are so few companies in the field,” noted Stein.
“It’s a tough area for clinical development. But once you get through, there’s an opportunity for that drug to be used because of the weaknesses of currently available treatments and preventatives.”
Cover illustration by Anastasiia Slynko, images via Shutterstock.